Morphine rescue doses in cancer pain management

Dr Vincent Vandenhaute

The use of opioids in pain relief for cancer patients is nowadays well documented. It is as important to correctly follow the titration rules in long term maintenance therapy as it is to manage the morphine rescue doses in the case of breakthrough pain. This article examines these two complementary aspects in the treatment of cancer pain. The use of fast-acting fentanyl, which recently has become commercially available in Belgium, is also discussed.

Treatment of severe cancer pain with WHO pain relief ladder analgesics of step 1 (paracetamol, acetylsalicylic acid) or step 2 (Codeine, Tramadol…) often turns out to be inadequate. In that case, 24 hour coverage with powerful step 3 analgesic opioids becomes a necessity. Often, the patient will also need additional analgesics or rescue doses.

Maintenance opioid therapy

The emergence of new, slow release dosage forms has simplified round-the-clock morphine maintenance therapy and has improved patient involvement and comfort. Patients can now benefit from the controlled release of the opioid by taking oral tablets every 12 hours, or by applying skin patches to be replaced every 72 hours.

Prescription conditions

There are two fundamental rules in the prescription of maintenance opioid therapy.

– The initiation of a treatment with morphine must strictly observe the titration rule. This means looking for the optimal opioid dose to provide effective and well tolerated analgesia by progressively increasing (or reducing) the dose. Clinical experience in palliative care has shown that the optimal dose cannot be determined in advance and that it must be personalized for each patient.The objective is to strike a balance between under-dosing, thus not providing adequate pain relief, and over-dosing, which could lead to opioid intoxication.

– Regardless of the method of administration selected, and unless contra-indicated for any medical reasons, the patient should strictly respect the dosage and schedule of the treatment as prescribed by the physician, even when the patient says “not to feel any pain”.

In practice, a treatment with opioids always starts at the low end of the dosing range. The dose should be increased gradually, until there is adequate pain relief. It is not uncommon that maintenance therapy will need to be re-evaluated, “re-titrated”, at a later stage, once it is well-established. Maintenance opioid therapy is not static, in particular because of the evolution of the disease itself.

Available molecules

Morphine, oxycodone, hydromorphone and fentanyl are the most frequently used opioids in palliative care. These pure μ-opioid receptor agonists are classified as step 3 drugs on the WHO ladder (Table 1) and therefore have no ceiling effect. Some examples:

– fentanyl skin patches, to be replaced every 72 hours;

– slow-release morphine, oxycodone, and hydromorphone tablets, to be taken every 12 hours;

– oxycodone/naloxone combination tablets to be taken every 12 hours. The addition of naloxone reduces opioid-induced constipation, but at a high dose the beneficial effect might be impaired. It is therefore not recommended to administer more than 40 mg oxycodone/20 mg naloxone per 24 hours.

The rescue dose

The appearance of acute nociceptive pain in cancer patients with a round-the-clock opioid medication requires the use of a supplemental dose of opioids with an immediate release action. This is called a rescue dose. These supplements are administered discontinuously; the treatment is given “on demand, rather than “by the clock”.Palliative care has a long tradition of using such sequential morphine rescue doses for the relief of breakthrough pain. Managing painful symptoms is of course one of the main objectives in palliative care and pain is considered to be a medical urgency. The use of rescue doses, as well as the main guidelines when prescribing them, is described below.

1. The calculation of the rescue dose follows well-documented rules. These will be explained in detail in the next chapter.

2. Rescue doses should be prescribed proactively from the start of the maintenance treatment with morphine, as breakthrough pain may occur at any moment. The first, planned response to a severe pain attack is the administration of a rescue dose. During the titration phase of the maintenance therapy, the use of the rescue dose offers an important advantage as it allows to start with a low dosed maintenance medication to avoid an overdose, while at the same time any breakthrough pain can be controlled in a satisfactory manner.

3. Repeated breakthrough pains often signal the need to increase the dosage of the maintenance treatment.Normally, the use of 3 to 4 rescue doses within a 24 hour period is interpreted as a sign that the dose of the maintenance opioid therapy should be increased by about 30%. However, this should not be done in a rush.Thanks to the availability of rescue doses it is possible to spread the evaluation of the daily need for the opioid maintenance treatment (titration) over a few of days, without the patient suffering from pain. Such a controlled approach is to be recommended in particular to avoid overdosing when using half-life opioids such as fentanyl skin patches. Patients sometimes repeatedly ask for rescue doses, irrespectively of the dosage of the maintenance therapy, because they obtain relief from its use.

4. The interval between two rescue doses will be determined by the physician. This will typically be a four hour interval which corresponds to the activity time of immediate release opioids. An interval of two hours is also acceptable when faced with significant pain episodes.

5. This on demand but “controlled” use of the opioid rescue dose allows patients to co-manage their pain. If the patient is at home, it is important to inform the patient and his entourage about this process and to urge them to use a logbook to keep track of the rescue doses administered.

6. In order to avoid induced pain, for example during manipulations, therapeutic interventions or transport, it is possible to administer the rescue dose as a preventive measure. In such cases, the preventative dose should given 30 to 60 minutes before the event if using oral morphine and 20 minutes before if using parenteral morphine.

7. We should never forget to continuously evaluate the pain experienced by the patient. In case of continuous pain even with a combination of maintenance therapy + rescue dose, the physician should research the existence of additional etiologies such as neuropathic pain, bone pain, infection or inflammation, wound-related pain, and faecal impaction… These conditions require a specific, non-morphine treatment and sometimes etiological treatment.

8. Also, we should never forget the impact mental suffering has on the patient´s pain perception.

Equianalgesics and rescue dose calculation

Identical molecules

Traditionally when the maintenance therapy and the rescue dose use identical opioid molecules, the value of the rescue dose is determined by calculating one-sixth or one-twelfth of the total daily dose of morphine over 24 hours. The actual tendency is to select a rescue dose value that is close to one-sixth in case this dose is weak, and close to one-tenth if it is strong. In general, the minimal dose in adults is equivalent to 5 mg oral morphine. Daily practice, underpinned by research, has shown that there is no overdose risk with this technique of calculating the rescue dose(1,2). An equianalgesic calculation should nonetheless be carried out whenever a rescue dose is selected with a different administration method than that of the basic medication.The conversion rule is as follows:

– the ratio of subcutaneous morphine compared to oral morphine is 1÷2;

– the ratio of intravenous morphine compared to oral morphine is 1÷3;

Example: 30 mg PO morphine = 15 mg SC morphine = 10 mg IV morphine

NOTE: The ratio between the different parenteral routes and the oral route is specific to each opiate.

Different molecules

When the opiates used in the basic medication and the rescue dose are different, the calculation is more complex. In-depth equianalgesic knowledge is required. Despite differences in the strength of the doses, pure µ receptor agonist opiates (WHO step 3) all have an identical analgesic potential that is comparable to morphine which is used as a reference standard. It suffices to adjust the dose of one of these molecules with respect to another molecule to obtain an identical analgesic strength. This process is called equianalgesics. The equianalgesic calculation of the opioid molecules essentially depends on two parameters: receptor affinity, which determines the notion of “strength”, and the bioavailability of each of those molecules. The generally accepted conversion guidelines of class 3 opioids are:

Example 2: For a patient taking an 8 mg hydromorphone Slow Release capsule twice a day, the hydromorphone Immediate Release rescue dose in case of breakthrough pain will be between 1.6 mg and 2.7 mg, that is to say a tablet of 2.6 mg IR.

Example 3: For a patient with a 75 µg/h transdermal fentanyl patch, the calculated rescue dose of oral oxycodone will be between 6 mg and 10 mg. If the physician opts for a subcutaneous morphine injection, the rescue dose to be administered will be between 9 mg and 15 mg.

It is clear that the use of different opioid products makes the calculation more complex. This is why conversion tables exist (Table 2) and why Orthodose®, a software specially developed for the calculation of rescue doses, was developed. Orthodose has been designed to make it easier to calculate the rescue dose in practice, in particular when different molecules and routes of administration are used.

Comments

– Adjustment of the rescue dose may be required due to inter-individual variability.

– Tablets containing a combination of oxycodone and naloxone have a ratio that is identical to that of oxycodone on its own in the equianalgesic calculation of the round-the-clock medication.However, these can never be used in the treatment of breakthrough pain.

Fast-acting fentanyl

Fentanyl, a pure µ receptor opioid agonist, has two characteristics that differentiate it from all other opioids of step 3, with the exception of methadone:

– it is a lipophilic opioid which allows for its excellent absorption via transcutaneous and transmucosal routes. The transcutaneous route has led to the development of extended release patches in the basic medication. Transmucosal administration has led to the development of fast-acting sublingual tablets and nasal sprays, avoiding first-pass liver metabolism;

– a clearance, primarily at the hepatic level through the cytochrome P3A4, with inactive metabolites. As less than 10% of its clearance is by renal excretion, fentanyl is an appropriate choice in the case of renal failure.

Indication

Fast-acting fentanyl is used exclusively for the relief of breakthrough pain in cancer patients. This treatment (rescue dose) is therefore supplementary to the round-the-clock maintenance therapy.

Contraindications

– Non-cancer pain.

– Maintenance therapy with morphine medication started less than a week ago.

– Dose of maintenance morphine therapy is less than the equivalent of 60 mg of oral morphine per 24 h.

– Patient is younger than 18 years.

Prescription method

In contrast to the normal practice with morphine rescue doses, the use of fast-acting fentanyl must follow precise titration rules that are fentanyl-specific… It is therefore not calculated based on the 24 hour maintenance opioid therapy dose. For each patient and for each type of fast-acting fentanyl one should start with the lowest available dose. As with any titration, the optimal dosage for each patient will only be determined by upward titration, after administering increasing doses when breakthrough pain occurs… Each patient has his or her own optimal dose. In addition, there is no direct dosage equivalent between the different types of fentanyl products. It will therefore be necessary to start “from scratch”, i.e. from the smallest dose, when switching from one form of fentanyl to another. For a better understanding of titration schemes, consider that with fast-acting fentanyl a rescue dose can be composed of one or two doses of fentanyl, in the latter case taken with an interval of 10 minutes (when using Instanyl®) to 30 minutes (when using Abstral®).

Titration of sublingual tablets

When administering Abstral®, a first sublingual tablet of the lowest dose, in this case 100 µg of fentanyl is administered at the onset of the breakthrough pain. If adequate analgesia is not obtained after 15 to 30 minutes, the patient may take a second tablet, with a dosage determined by an Abstral®-specific titration scheme (Table 3). A single rescue-dose of fentanyl therefore consists of a first tablet, possibly followed by a second. Patients must wait at least 4 hours before taking the next rescue dose in case of another breakthrough pain episode. The first tablet of the subsequent rescue-dose will be equivalent to the strength of the previous rescue-dose, and thus possibly to the sum of the two tablets. If there is no adequate pain relief achieved with this subsequent dose of Abstral® within 15 to 30 minutes, a second tablet might be taken. The dosage of this new tablet is as indicated in the titration scheme in table 3.An Abstral® rescue dose must not exceed 800 µg fentanyl. Limit the number of Abstral® rescue doses to 4 per day. If this is not enough, an increase in the maintenance therapy must be considered.

Table 3: Abstral® titration table.

Dose in µg of the first Abstral® sublingual tablet

Dose in µg of the second Abstral® sublingual tablet

To take at the onset of breakthrough pain

To take as a supplement, 15 to 30 minutes after the first tablet,
if the pain persists

100 µg

100 µg

200 µg

100 µg

300 µg

100 µg

400 µg

200 µg

600 µg

200 µg

800 µg

-

Titration of fentanyl nasal spray

When using Instanyl® in case of breakthrough pain, start with administering the weakest spray (in one nostril), that is to say, one dose of 50 µg fentanyl (Table 4). A second dose of the same strength can be administered after an interval of minimally 10 minutes if no adequate pain relief is achieved. Patients should wait at least 4 hours before taking the next rescue dose in case of another breakthrough pain episode, with a maximum of 4 rescue doses per day.

Table 4: Instanyl® titration table.

If the patient regularly needs more than 2 doses of 50 μg per rescue dose, the physician may increase the strength of the spray to 100 μg. If there is no adequate pain relief after 10 minutes, another dose of the same strength may be administered; the total rescue dose this time therefore contains 200 μg fentanyl. The maximum of nasal fentanyl per
rescue dose is 400 μg. The maximum number of rescue doses is 4 per day. If this is not enough, an increase in the maintenance opioid therapy must be considered.

Cost

The important additional costs that the use of transmucosal fentanyl implies needs to be taken into account. In Belgium these medicaments are not reimbursed. A box of 10 tablets of Abstral® costs 72 € and 10 doses of Instanyl® spray cost 105 €, which means in practice that the majority of our patients cannot afford to buy these products.

In Belgium

In English-speaking countries, the rescue dose with fentanyl has been put firmly on the scene, in particular in the specialised press. In our daily practice in Belgium, its cost and the need for a titration period have prevented it from becoming a treatment of first choice. Its fast action(5), estimated between 5 and 15 minutes, in comparison with other oral opioid substances does not seem to be a decisive factor in everyday medical practice. In English-speaking countries, special attention is given to the breakthrough pain syndrome, the recurring paroxysmal pain experienced by some patients, which reaches its peak within minutes to disappear again after 10 to 15 minutes. For these patients, transmucosal fentanyl is an alternative to the rescue doses administered by parenteral opioid injections. We should also consider its use in cases of renal failure. Further research is needed to shed more light on this issue and to pursue these ideas in more detail.

Conclusion

The new long-acting pharmaceutical dose forms have significantly increased patient comfort and simplified the prescription and administration of opioids.

Opioid rescue doses are needed in the treatment of breakthrough pain. The co-existence of different molecules requires a good understanding of equianalgesic dosing. Equianalgesic calculation will be facilitated by the use of tables and/or the Orthodose software.

The use of fast-acting fentanyl calls for a new approach since it involves titration of the rescue-dose.

To remember:

1. Maintenance opioid therapy (M+) is started at a low dose that is gradually increased depending on the patient’s need. It can always be adjusted afterwards.

2. Always prescribe a rescue dose M+ when initiating maintenance therapy. It is taken on an “as needed” basis (with ≥ 4 hour intervals), or as a preventative measure (30 min) before a therapeutic intervention.

3. The strength of the rescue dose is ≥ 5 mg of oral M+. It is equivalent to 1/6 to 1/10 of the 24 hour total dose of the maintenance therapy.